The present invention relates to a process for preparing an urethane compound for medical instruments. More particularly, the present invention relates to a process for easily preparing an urethane compound (macromonomer) showing high safety, which is very useful for a material of medical instruments represented by optical materials such as a contact lens material and an intraocular lens material. Furthermore, the present invention relates to a process for preparing an urethane compound while molecular weight of the compound is controlled.
At present, various urethane compounds such as urethane foam, urethane rubber, adhesives and polyurethane synthetic fiber are industrially used.
In the absence of a catalyst or in the presence of a compound such as an organic metal compound or a tertiary amine, hydroxyl group is reacted with isocyanate group to form urethane bond. Particularly, from the viewpoint of high catalytic activity, the organic metal compounds are generally used. Among them, an organic tin compound is well known.
However, it is considered that the organic tin compound which is generally known as a compound showing high toxicity must not be used as a catalyst for preparation of urethane materials when the urethane materials are applied for medical instruments which are used in living organism or by contacting with living organism. The organic tin compound is recognized as a distraction substance for endocrine (environmental hormone) which is recently topical substance. Accordingly, some catalysts other than organic tin compounds are earnestly necessitated.
From the viewpoint of mechanical strength and excellent oxygen permeability, urethane bond-containing siloxane compounds (macromonomers) have been examined for the use as medical instruments, in particular, optical materials such as a contact lens material and an intraocular lens material (Japanese Unexamined Patent Publication No. 22487/1979, Japanese Unexamined Patent Publication No. 121826/1994, U.S. Pat. No. 5,451,617 and the like). However, because the siloxane compounds disclosed in these references are prepared by using the organic tin compounds almost, these siloxane compounds are not suitable as medical materials on the basis of the above reasons. Even if purification of the siloxane compound is carried out, the organic tin compounds remain within the siloxane compound.
Usually, the above urethane bond-containing siloxane compounds (macromonomers) have been prepared by finally introducing a polymerizing group in a polyfunctional polysiloxane which is a main chain through urethane bond (Japanese Unexamined Patent Publication No. 179217/1986, Japanese Unexamined Patent Publication No. 35014/1991 and the like). However, when this method is employed, it is inevitable that the polymerizing group is inestimably and repeatedly introduced in the polyfunctional polysiloxane which is a main chain through urethane bond. As a result, molecular weight of the obtained siloxane compound becomes higher than planned molecular weight. Accordingly, there is a problem that clear understanding for structure of the obtained compound is difficult.
Because the above siloxane compound becomes a high viscous solution according to its molecular weight or kind of reaction components, effective purification methods for the siloxane compound are not developed. So, it is very difficult to remove impurities such as the above catalyst and by-products, and crude siloxane compound is used. Accordingly, the use of the siloxane compounds has been feared from the viewpoint of safety, including the above problems.
An object of the present invention is to provide a process for easily preparing an urethane compound, in particular, while molecular weight of the compound is controlled, in the absence of a catalyst or in the presence of a catalyst showing lower toxicity instead of the conventional organic tin compounds.
This and other objects of the present invention will become apparent from the description hereinafter.
In accordance with the present invention, there is provided a process for preparing an urethane compound for medical instruments, characterized by reacting a hydroxyl compound (A) with an isocyanate compound (B) in the absence of a catalyst or in the presence of a reaction catalyst other than an organic tin compound to give an urethane compound (I).
According to the process of the present invention, an urethane compound showing high safety, which is very useful for a material of medical instruments represented by optical materials can be easily prepared, in particular, while molecular weight of the compound is controlled.
In the process for preparing an urethane compound for medical instruments, as mentioned above, the hydroxyl compound (A) is reacted with the isocyanate compound (B) to give an urethane compound (I) in the absence of the catalyst or in the presence of the reaction catalyst other than the organic tin compound in order to more accelerate this reaction.
In consideration of the use of the urethane compound as a material for medical instruments, preferable examples of the above reaction catalyst are an organic iron compound and an amine compound because of excellent safety.
Examples of the above organic iron compound are, for instance, iron(III) acetylacetonate and the like.
Examples of the above amine compound are, for instance, a cyclic tertiary amine such as triethylenediamine, an aliphatic tertiary amine such as trimethylamine or triethylamine, an aromatic tertiary amine such as dimethylaniline or triphenylamine, and the like.
Because molecular weight of the urethane compound can be more sufficiently controlled, the organic iron compound is particularly preferable.
In order to sufficiently exhibit acceleration effect for the progress of reaction, it is desired that the amount of the reaction catalyst is, on the basis of weight, at least 1 ppm, preferably at least 30 ppm of the total amount of the hydroxyl compound (A) and the isocyanate compound (B). In order to prevent removal of the reaction catalyst from being finally difficult after the finish of reaction, it is desired that the amount of the reaction catalyst is, on the basis of weight, at most 10000 ppm, preferably at most 3000 ppm of the total amount of the hydroxyl compound (A) and the isocyanate compound (B). The amount of the reaction catalyst can be suitably adjusted within the above range according to kind of the hydroxyl compound (A) and the isocyanate compound (B) in urethane reactions (i) and (ii) as mentioned below.
In the present invention, it is desired that the above compound (I) is prepared by, for instance, the following two-step urethane reactions (i) and (ii).
At first, in the urethane reaction (i), at least one member of dihydroxyl compounds (A-2) is used as the hydroxyl compound (A) and at least one member of diisocyanate compounds (B-2) is used as the isocyanate compound (B), so the dihydroxyl compound (A-2) is reacted with the diisocyanate compound (B-2). As a result, at least two urethane bonds are formed between hydroxyl group in the dihydroxyl compound (A-2) and isocyanate group in the diisocyanate compound (B-2).
When 1 mole of the dihydroxyl compound (A-2) is reacted with 2 moles of the diisocyanate compound (B-2), two urethane bonds are formed and a compound having isocyanate groups in its both ends respectively through two urethane bonds is synthesized. On the other hand, when 2 moles of the dihydroxyl compound (A-2) is reacted with 1 mole of the diisocyanate compound (B-2), two urethane bonds are formed and a compound having hydroxyl groups in its both ends respectively through two urethane bonds is synthesized.
In the urethane reaction (i), the dihydroxyl compound (A-2) is not limited to one member and the diisocyanate compound (B-2) is also not limited to one member. So, at least two members of each compound can be used with suitable combination. Accordingly, in a compound synthesized in the urethane reaction (i), units derived from at least two members of the dihydroxyl compounds (A-2) and/or units derived from at least two members of the diisocyanate compounds (B-2) can be included.
The urethane reaction (i) may be finished only one time or repeatedly carried out stepwise. When the urethane reaction (i) is repeatedly carried out stepwise, the number of formed urethane bond is increased on the basis of the number of reaction.
Typical examples of the dihydroxyl compound (A-2) are, for instance, a hydroxyl group-containing polysiloxane compound represented by the formula (I): 
wherein each of R1 and R2 is independently an alkylene group having 1 to 20 carbon atoms, each of R3, R4, R5, R6, R7 and R8 is independently a linear alkyl group having 1 to 20 carbon atoms, a branched alkyl group having 3 to 20 carbon atoms or a cyclic alkyl group having 3 to 20 carbon atoms, which may be substituted with fluorine atom, x is an integer of 1 to 1500, y is an integer of 1 to 1499, and xe2x80x9cx+yxe2x80x9d is an integer of 1 to 1500; and the like.
In the above formula (I), each of R1 and R2 is preferably an alkylene group having 1 to 10 carbon atoms. Each of R3, R4, R5, R6, R7 and R8 is preferably a linear alkyl group which may be substituted with fluorine atom, having 1 to 5 carbon atoms, a branched alkyl group which may be substituted with fluorine atom, having 3 to 5 carbon atoms, or a cyclic alkyl group which may be substituted with fluorine atom, having 3 to 5 carbon atoms. Also, x is preferably an integer of 1 to 500, y is preferably an integer of 1 to 499, and xe2x80x9cx+yxe2x80x9d is preferably an integer of 1 to 500.
In addition, as the above dihydroxyl compound (A-2), a dihydroxyl compound having hydroxyl groups in its both ends, such as a polyalkylene glycol such as polyethylene glycol or polypropylene glycol; and the like are exemplified.
Typical examples of the diisocyanate compound (B-2) are, for instance, a diisocyanate compound represented by the formula (II):
Oxe2x95x90Cxe2x95x90Nxe2x80x94R10xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(II)
wherein R10 is a linear aliphatic hydrocarbon group having 1 to 20 carbon atoms, a branched hydrocarbon group having 2 to 20 carbon atoms, a cyclic aliphatic hydrocarbon group having 3 to 20 carbon atoms or an aromatic hydrocarbon group having 6 to 20 carbon atoms; and the like.
In the above formula (II), R10 is preferably a linear aliphatic hydrocarbon group having 1 to 12 carbon atoms, a branched hydrocarbon group having 2 to 12 carbon atoms, a cyclic aliphatic hydrocarbon group having 3 to 12 carbon atoms or an aromatic hydrocarbon group having 6 to 12 carbon atoms.
Concrete examples of the diisocyanate compound (B-2) are, for instance, ethylenediisocyanate, isophoronediisocyanate, 1,6-hexamethylenediisocyanate, 1,2-toluenediisocyanate, 1,4-toluenediisocyanate, xylylenediisocyanate, bis(2-isocyanatethyl)fumarate, 1,5-naphthalenediisocyanate, cyclohexyl-1,4-diisocyanate, 4,4xe2x80x2-dicyclohexylmethanediisocyanate, diphenylmethane-4,4xe2x80x2-diisocyanate, 2,2,4-(2,4,4)-trimethylhexane-1,6-diisocyanate and the like.
It is considered that the ratio of the dihydroxyl compound (A-2) to the diisocyanate compound (B-2) in the urethane reaction (i) considerably effects for the amount of prepared by-products, the amount of residual non-reacted compounds, and molecular weight and molecular weight distribution of the aimed urethane compound.
In the urethane reaction (i), from the viewpoint of reduction of residual non-reacted isocyanate groups, it is desired that the total amount of hydroxyl group in the dihydroxyl compound (A-2) based on 1 mole of isocyanate group in the diisocyanate compound (B-2) is at least 0.4 mole, preferably at least 0.6 mole, more preferably at least 0.8 mole. From the viewpoint of reduction of residual non-reacted dihydroxyl compound (A-2) which not bonds to the diisocyanate compound (B-2) through urethane bond, it is desired that the total amount of hydroxyl group in the dihydroxyl compound (A-2) based on 1 mole of isocyanate group in the diisocyanate compound (B-2) is at most 2 moles, preferably at most 1.5 moles, more preferably at most 1.25 moles.
The amount of the dihydroxyl compound (A-2) and the diisocyanate compound (B-2) is adjusted within the above range. Then, these compounds are reacted by stirring and mixing with each other.
In the above reaction, reaction temperature and reaction time are not particularly limited and suitably adjusted according to kind and combination of each compound. In order to prevent insufficient reaction, it is desired that reaction time is at least 1 minute, preferably at least 30 minutes, and reaction temperature is at least xe2x88x9230xc2x0 C., preferably at least 0xc2x0 C. In order to prevent polymerization due to polymerizable compounds during reaction, it is desired that reaction time is at most 100 hours, preferably at most 50 hours, and reaction temperature is at most 150xc2x0 C., preferably at most 100xc2x0 C.
Then, in the urethane reaction (ii),
(a) the compound having isocyanate groups in its both ends obtained in the above urethane reaction (i) is reacted with at least one member of monohydroxyl compounds (A-1) as the hydroxyl compound (A) to form urethane bond; or
(b) the compound having hydroxyl groups in its both ends obtained in the above urethane reaction (i) is reacted with at least one member of monoisocyanate compounds (B-1) as the isocyanate compound (B) to form urethane bond. By each reaction, the compound (I) having at least four urethane bonds is prepared.
Because molecular weight of the aimed urethane compound can be controlled and structure of this compound can be exactly clarified, it is desired that the above two-step urethane reactions (i) and (ii) are carried out in the present invention.
In the above reaction (a), the monohydroxyl compound (A-1) to be reacted with the compound having isocyanate groups in its both ends is not limited to one member. At least two members of the monohydroxyl compounds (A-1) can be suitably used. In the above reaction (b), the monoisocyanate compound (B-1) to be reacted with the compound having hydroxyl groups in its both ends is not limited to one member. At least two members of the monoisocyanate compounds (B-1) can be suitably used. As a result, the compound (I) obtained in the reaction (a) or (b) can contain the unit derived from two members of the monohydroxyl compounds (A-1) or the unit derived from two members of the monoisocyanate compounds (B-1).
In accordance that the above urethane reaction (i) is finished only one time or repeatedly carried out stepwise, the number of urethane bond and the number of unit (block) derived from each component in the compound (I) synthesized in the urethane reaction (ii) vary. As a result, for instance, a diblock-type compound (I) is synthesized. Because chain length of each segment in the diblock-type compound (I) is controlled, various different effects can be exhibited.
Typical examples of the monohydroxyl compound (A-1) are, for instance, a compound having hydroxyl group and an active unsaturated group, such as a hydroxyalkyl(meth)acrylate, allyl alcohol, vinylbenzyl alcohol, monohydroxyl fumarate, monohydroxyl maleate or monohydroxyl itaconate; and the like.
In consideration of copolymerizability of the aimed compound (I) with the other copolymerizable compound having an active unsaturated group, among the above exemplified compounds, a hydroxyalkyl(meth)acrylate is preferable. Concrete examples of the hydroxyalkyl(meth)acrylate are, for instance, 2-hydroxyethyl(meth)acrylate, 2-hydroxypropyl(meth)acrylate, 3-hydroxypropyl(meth)acrylate, 4-hydroxybutyl (meth)acrylate and the like.
Typical examples of the monoisocyanate compound (B-1) are, for instance, a compound having isocyanate group and an active unsaturated group, such as allylisocyanate, vinylisocyanate, vinylbenzylisocyanate or 2-isocyanatethyl(meth)acrylate; and the like.
When the above reaction (b) in the urethane reaction (ii) is carried out, because the number of urethane bond in the compound (I) can be controlled and mechanical strength can be imparted to the compound (I), it is desired that a compound containing a monoisocyanate compound (B-1-1) prepared by reacting the diisocyanate compound (B-2) with the monohydroxyl compound (A-1) is used as the monoisocyanate compound (B-1). It is particularly desired that only the monoisocyanate compound (B-1-1) is used as the monoisocyanate compound (B-1).
In the reaction (a), it is desired that the ratio of the compound having isocyanate groups in its both ends to the monohydroxyl compound (A-1) is adjusted so as to react isocyanate groups in the compound having isocyanate groups in its both ends with almost neither more nor less hydroxyl groups in the monohydroxyl compound (A-1). For instance, from the viewpoint of reduction of residual non-reacted isocyanate groups, it is desired that the amount of hydroxyl group in the monohydroxyl compound (A-1) based on 1 mole of isocyanate group in the compound having isocyanate groups in its both ends is at least 1.0 mole, preferably at least 1.1 moles, more preferably at least 1.2 moles. From the viewpoint of reduction of residual non-reacted monohydroxyl compound (A-1) which not bonds to the compound having isocyanate groups in its both ends through urethane bond, it is desired that the amount of hydroxyl group in the monohydroxyl compound (A-1) based on 1 mole of isocyanate group in the compound having isocyanate groups in its both ends is at most 2.0 moles, preferably at most 1.5 moles, more preferably at most 1.5 moles.
The amount of the compound having isocyanate groups in its both ends and the monohydroxyl compound (A-1) is adjusted within the above range. Then, these compounds are reacted by stirring and mixing with each other.
In the above reaction, reaction temperature and reaction time are not particularly limited and suitably adjusted according to kind and combination of each compound. In order to prevent insufficient reaction, it is desired that reaction time is at least 1 minute, preferably at least 30 minutes, and reaction temperature is at least xe2x88x9230xc2x0 C., preferably at least 0xc2x0 C. In order to prevent polymerization due to polymerizable compounds during reaction, it is desired that reaction time is at most 100 hours, preferably at most 50 hours, and reaction temperature is at most 150xc2x0 C., preferably at most 100xc2x0 C.
In the reaction (b), it is desired that the ratio of the compound having hydroxyl groups in its both ends to the monoisocyanate compound (B-1) is adjusted so as to react hydroxyl groups in the compound having hydroxyl groups in its both ends with almost neither more nor less isocyanate groups in the monoisocyanate compound (B-1-1). For instance, from the viewpoint of reduction of residual non-reacted hydroxyl groups, it is desired that the amount of isocyanate group in the monoisocyanate compound (B-1) based on 1 mole of hydroxyl group in the compound having hydroxyl groups in its both ends is at least 1.0 mole, preferably at least 1.1 moles, more preferably at least 1.2 moles. From the viewpoint of reduction of residual non-reacted monoisocyanate compound (B-1) which not bonds to the compound having hydroxyl groups in its both ends through urethane bond, it is desired that the amount of isocyanate group in the monoisocyanate compound (B-1) based on 1 mole of hydroxyl group in the compound having hydroxyl groups in its both ends is at most 2.0 moles, preferably at most 1.75 moles, more preferably at most 1.5 moles.
The amount of the compound having hydroxyl groups in its both ends and the monoisocyanate compound (B-1) is adjusted within the above range. Then, these compounds are reacted by stirring and mixing with each other.
In the above reaction, reaction temperature and reaction time are not particularly limited and suitably adjusted according to kind and combination of each compound. In order to prevent insufficient reaction, it is desired that reaction time is at least 1 minute, preferably at least 30 minutes, and reaction temperature is at least xe2x88x9230xc2x0 C., preferably at least 0xc2x0 C. In order to prevent polymerization due to polymerizable compounds during reaction, it is desired that reaction time is at most 100 hours, preferably at most 50 hours, and reaction temperature is at most 150xc2x0 C., preferably at most 100xc2x0 C.
When the compound (I) is prepared by the urethane reaction (i) or (ii), in order to prevent active unsaturated groups in each compound from polymerizing with each other, it is desired that a polymerization inhibitor is suitably used.
Examples of the polymerization inhibitor are, for instance, a stable radical compound; an addition inhibitor such as oxygen, a benzoquinone derivative or a nitro compound; and the like. Hydroquinone, p-methoxyphenol and butylhydroxytoluene are preferably exemplified. It is desired that the amount of the polymerization inhibitor based on 100 parts by weight (hereinafter referred to as xe2x80x9cpart(s)xe2x80x9d) of all the compounds having an active unsaturated group is about 0.01 to 1 part.
The hydroxyl compound (A) can be reacted with the isocyanate compound (B) in the absence of a solvent or in the presence of an organic solvent.
Examples of the organic solvent are, for instance, tetrahydrofuran, benzene, toluene, acetonitrile, methylene chloride and the like.
When the organic solvent is used, in order to remove the fear that it becomes difficult to react the hydroxyl compound (A) with the isocyanate compound (B), and so, the yield of the compound (I) is lowered, it is desired that the total concentration of the hydroxyl compound (A) and the isocyanate compound (B) in the organic solvent is at least 0.01 mol/L, preferably at least 0.1 mol/L. That is, the amount (volume) of the organic solvent can be calculated according to the total concentration of the hydroxyl compound (A) and the isocyanate compound (B). A reaction solution composed of the hydroxyl compound (A), the isocyanate compound (B) and the organic solvent is sufficiently stirred or shaken so that the reaction uniformly proceeds.
In accordance with the above steps, the aimed urethane compound (I) can be prepared. After finishing the reaction for preparing the compound (I), it is desired that the compound (I) is purified by removing non-reacted compounds, compounds having lower molecular weight (by-products) and catalysts.
For purification of the compound (I), an organic solvent is preferably used. In addition, the compound (I) can be purified by using a supercritical fluid with referring to xe2x80x9cPolymer Applications, Vol. 43, No. 11, p. 38 (1994)xe2x80x9d.
As the above organic solvent for purification, a solvent which can dissolve the non-reacted compounds, by-products and catalysts or can dissolve the compound (I) is used. Typical examples of the organic solvent are, for instance, methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, methylene chloride, hexane and the like. These can be used alone or in admixture thereof. In order to more effectively purify the compound (I), a mixed solvent of hexane and methanol and a mixed solvent of hexane and acetonitrile are preferably used.
In order to sufficiently remove the non-reacted compounds, by-products and catalysts, it is desired that the amount of the organic solvent is, on the basis of the volume, at least {fraction (1/20)} time, preferably at least {fraction (1/10)} time of the amount of the compound (I). In order to prevent the amount of waste fluid from increasing after purification, it is desired that the amount of the organic solvent is, on the basis of the volume, at most 20 times, preferably at most 10 times of the amount of the compound (I).
As the above supercritical fluid for purification, a fluid in the supercritical state, such as carbon dioxide, ethane or propane may be cited.
Condition as to purification with the supercritical fluid varies according to molecular weight and chemical structure of the compound (I). So, the condition cannot be sweepingly determined. For instance, it is desired that treating pressure is 5 to 100 MPa, and treating temperature is 0xc2x0 to 10xc2x0 C.
In order to more effectively extract the compounds having lower molecular weight, an auxiliary for extraction can be used during purification of the compound (I) with the supercritical fluid. Examples of the auxiliary for extraction are, for instance, acetonitrile, methanol and the like.
According to the process of the present invention, the urethane compound showing high safety, which is very useful for a material of medical instruments represented by optical materials can be easily prepared, in particular, while molecular weight of the compound is controlled.